The overall goal of this proposal is to relate observations at the DNA level to the distribution of coronary heart disease (CHD) in the population at large. We propose to study measurements of the genes coding for the apolipoproteins and the low density lipoprotein (LDL) receptor, gene products (apolipoproteins), cholesterol (C), triglycerides (TG), high density lipoprotein cholesterol (HDL-C) and CHD endpoints from 2259 individuals in 300 three-generation pedigrees ascertained independently of their disease or risk factor status from the Rochester, MN, population. There are currently no data available to support the hypothesis that measures of DNA variation will improve the prediction of CHD endpoints beyond that provided by the quantitative measurements of the apolipoproteins (apos), C, TG, and HDL-C. We will obtain an estimate of the information about CHD that resides in the gene loci coding for the apos and the LDL receptor that is independent of information obtained from the quantitative measurements of the apos, C, TG, and HDL-C levels. Detection of such pleiotropic effects of DNA variations not expressed in the traditional lipid and lipoprotein risk factor phenotypes would support the argument for a molecular genetic approach to the epidemiology of CHD. Five aims are proposed that present a logical progression of studies to link variation in DNA to the occurrence of CHD. In Aim 1 we will characterize variation at the DNA level using restriction fragment length polymorphisms and at the protein level by isoelectric focusing. Aim 2 defines the relationships in the population between the apolipoproteins (measured by polyclonal and monoclonal antibodies), C, TG, HDL-C phenotypes and estimates the effects of age, sex, smoking, drug use and obesity on these relationships. Aim 3 estimates the fraction of the interindividual variation in the apos that is attributable to gene loci coding for these molecules. Aim 4 estimates the fraction of interindividual variation in C, TG, and HDL-C that is attributable to gene loci coding for the apos and the LDL receptor. And, Aim 5 will determine whether genotypic variation for the gene loci coding for the apo and the LDL-receptor contributes to the prediction of CHD beyond that provided by the effects of these gene loci on the interindividual variation in the apos, C, TG, and HDL-C.